Chemokines are a family of cytokines that regulate the adhesion and transendothelial migration of leukocytes during an immune or inflammatory reaction (Mackay C. R., Nat. Immunol., 2001, 2:95; Olson et al., Am. J. Physiol. Regul. Integr. Comp. Physiol., 2002, 283:R7). They also regulate trafficking and homing of T cells and 13 cells, contributing to the development of lymphopoietic and hematopoietic systems (Ajuebor et al., Biochem. Pharmacol., 2002, 63:1191).
Approximately 50 chemokines have been identified in humans. They can be classified into 4 subfamilies, i.e., CXC, CX3C, CC, and C chemokines, based on the positions of the conserved cysteine residues at the N-terminal (Onuffer et al., Trends Pharmacol Sci., 2002, 23:459). Stromal-derived factor-1 (SDF-1), a CXC chemokine, plays key roles in trafficking and retention of malignant stem cells in the bone marrow microenvironment (Nervi et al., Blood, 2009, 24:6206-6214), as well as in homing and mobilization of hematopoietic stem cells and endothelial progenitor cells (Bleul et al., J. Exp. Med., 1996, 184:1101; and Gazzit et al., Stem Cells, 2004, 22:65-73). The physiological function of SDF-1 is mediated by the type 4 CXC chemokine Receptor (CXCR4).
The protective tumor microenvironment is increasingly being recognized as a critical factor in resistance of chemotherapeutic agents. A chemotherapeutic agent is a drug that inhibits cancer cell growth. There is a need to develop agents that mobilize tumor cells from their protective microenvironment to the peripheral blood and make them more accessible to chemotherapeutic agents.
Heart failure in patients who have survived myocardial infarction (MI) remains a major health problem. It is known that mobilizing hematopoietic stem cells, mesenchymal stem cells, and endothelial progenitor cells promotes cardiac functional recovery after MI. Thus, there is also a need to develop agents to mobilize such cells, thereby improving the heart function of post-MI patients.